There is some evidence about decreased neurotrophin production and
signaling in the brain playing a role in the unknown mechanism of
neurodegeneration in Parkinson's disease (PD) (1,2,3). Leptin is a
growth factor that is synthesized and released from adipocytes and plays
a principal role in food intake and body weight. There are leptin
receptors in the hypothalamic, thalamic, and extra-thalamic brain
regions, such as the cortex, hippocampus, brainstem, and cerebellum
(1,4). Two functionally distinct groups of dopaminergic neurons are rich
in leptin receptor expression in the brain (1,5,6): one is the medial
group located in the ventral tegmental area, which is known to help food
intake and reward pathways, while the other is the lateral group, namely
the dopaminergic neurons of the substantia nigra pars compacta, which
are involved in the modulation of peripheral motor control and,
specifically PD (1,5,6).

Learning and memory are functions of the hippocampus, and long-term
potentiation, a type of plasticity, takes place in this area. Some
studies have reported that the direct administration of leptin into the
hippocampus improves learning and memory (7,8). Moreover, low leptin
levels have been discovered in Alzheimer disease (AD) patients (9).
There are some important pathways in the brain that utilize dopamine
other than just the nigrostriatal and tubuloinfindubular pathway, namely
the mesocortical and mesolimbic pathways that link the ventral tegmental
area of the midbrain to the prefrontal cortex and to the limbic area,
respectively. In PD, the nigrostriatal pathway and the other two
abovementioned patients can be affected. Although there are some studies
in the literature about the relationship among weight loss, body fat
mass, and satiety with blood leptin levels in PD patients (10,11,12),
there is no study investigating the relationship between cognition and
blood leptin levels in PD.

Therefore, in the present study, we aimed to investigate the
relationship between blood leptin levels and the cognitive state of
Turkish PD patients using the validated form of the Montreal Cognitive
Assessment Scale in Turkey (MoCA-TR).

METHODS

Thirty patients with the diagnosis of idiopathic PD according to
the United Kingdom PD society brain bank criteria (13) and 30 healthy
controls with similar demographic features were enrolled into the study.
The subjects were recruited from the outpatient clinic of movement
disorders at Erenkoy Education and Research Hospital for Neurological
and Psychiatric Disorders in Istanbul, Turkey PD patients were evaluated
by the Unified Parkinson's disease rating scale (UPDRS) and the
Hoehn and Yahr scale (HY) for the stage and the severity of the disease.
The daily dose of dopaminergic medications taken by the patient was
recorded as the L-dopa equivalent daily dose (LEDD, mg/day) (14).
Patients who were unable to ambulate; those with systemic illnesses,
such as diabetes, thyroid disease, and neoplasia; those with psychiatric
diseases (psychosis and severe depression), which can interfere with the
cognitive test performance; those using any medication that may affect
body weight, namely some antidepressants, antipsychotics,
antihistamines, corticosteroids, diabetes medications; and those who had
major dietary restrictions were excluded. None of the patients presented
with nausea or anorexia due to dopaminergic medication, and none changed
their dietary habits throughout the whole study. None of the subjects
had undergone surgical treatment for PD. The controls subjects did not
have any past or present neurological, psychiatric, or metabolic
disorders that are known to cause an impairment to cognition. Any
subjects using medication that may affect body weight and that involved
major dietary restrictions were excluded.

At baseline, all the patients had their standing height and weight
measurements taken using a standard scale. Each patient's body mass
index (BMI) was then calculated as the weight (in kilograms) divided by
the square of their height (in meters) and classified as normal
(<25), overweight (25-29), or obese ([greater than or equal to]30).
At baseline, the waist circumference (WC) (in centimeters) was measured
at the level of maximum indentation over the abdomen.

On the day of the neurological examination and the body
measurements, a 5 mL fasting blood sample was obtained from each patient
between the times of 08.00 and 11.00 am. Serum was separated and stored
at -80[degrees]C until analysis. Leptin concentrations were analyzed by
DIAsource ImmunoAssays Human Leptin ELISA kit (DIAsource,
Louvain-la-Neuve, Belgium) by an investigator who was blinded to the
clinical criteria. This ELISA sandwiches human leptin between two
monoclonal antibodies reacting against different epitopes on the leptin
molecule.

The cognitive status of all the subjects was evaluated using the
MoCA-TR scale. Selekler et al. (15) translated the MoCA-TR test in 2010
to Turkish, which had some cultural and linguistic changes from the
original form. It was also validated with Parkinson's disease (PD)
in Turkey (16). MoCA-TR is a 30 point scale in which a higher score
indicates better cognition, and scores under 21 indicate a cognitive
dysfunction in the Turkish PD population (16). PD patients were on
dopamineric treatment during the study and evaluated in their
'on' state.

This study was approved by the Institutional Review Board and
informed written consent was obtained from all subjects.

Statistical Analyses

All statistical analyses were was performed using the Statistical
Package for the Social Sciences (IBM SPSS Statistics, New York, USA)
version 20. The independent sample t-test and Yates chi-square test were
used for the between-group comparisons. Correlations between serum
leptin and body weight, BMI, and UPDRS were performed using
Spearman's rank correlation coefficient (r). All the p values were
two-sided and the level of statistical significance was set at
p<0.05.

RESULTS

The mean age of the patients and controls were 59.37 [+ or -] 9.27
and 58.50 [+ or -] 9.85, respectively Five PD patients and eight
controls were women (Table 1). The mean HY stage of the patients was 2.2
[+ or -] 0.9. Ten patients were at Hoehn-Yahr stage I, nine were at
stage 2, eight were at stage 3, and three were at stage 4. The daily
total dopaminergic dose of the patients was 777 [+ or -] 408 mg.

Although the WC of the patients were significantly higher than the
controls (p=0.03), there was not any statistically significant
difference between BMI of PD patients and the controls (p=0.246).
Further, leptin levels did not differ between PD patients and the
controls (p=0.209), but PD patients had significantly lower MoCA-TR
scores than the control subjects (p=0.037).

In PD patients, leptin levels were significantly correlated with
weight (r=0.417, p=0.022), waist circumference (r=0.522, p=0.003), and
BMI (r=0.63I, p=0.00I) measurements (Table 2), but there was no
correlation between MoCA-TR scores and leptin levels (r=0.020, p=0.916)
(Table 2). There was no significant relationship between leptin levels
and UPDRS III or the total scores (r=-0.59, p=0.750; r=-0.75, p=0.69),
respectively. Also, the duration of the disease and the dose of
dopaminergic treatment was not correlated with leptin levels (r=0.104,
p=0.585 and r=0.19, p=0.30, respectively).

In the control group, there was no correlation of leptin levels
with body composition measurements or MoCA-TR scores (Table 2).

DISCUSSION

In the present study, the blood leptin levels of PD patients were
similar to normal controls, and they were not associated with cognition,
as assessed by MoCA-TR, or the degree of motor or functional impairment,
as assessed by UPDRS, or disease duration.

There are several reports in the literature evaluating leptin
levels and its relationship with weight in PD patients (10,11,12,17).
Lorefalt et al. (11) found that leptin was correlated with body fat mass
both in PD patients and in the controls, and they found the lower leptin
values in weight-losing PD patients could be related to their decreased
body fat mass (11).

Evidente et al. (12) found that mean serum leptin concentrations
were lower in PD patients with weight loss than in weight stable
patients, but this did not reach statistical significance. They
concluded that unintended weight loss in PD patients is unlikely to be
due to abnormal serum leptin concentrations (12). In our study we could
not find any statistically significant difference between the BMI of the
patients and of the controls, but leptin levels were significantly
correlated with weight, WC, and BMI in PD patients.

In two studies, it was shown that injecting leptin into the
hippocampus directly improved learning and memory performance (8,18). In
addition, the structure of some brain regions, such as the midbrain, the
hippocampus, and the hindbrain, was shown to be altered by leptin
(19,20,21,22). Also the neuroprotective actions of leptin have been
reported in some studies (23,24). Paz-Filho et al. (25) reported that
the substitution of leptin in a leptin-deficient child not only improved
the metabolic parameters but also had a markedly positive effect on
neurocognitive development (25). Because of these recent reports about
leptin and its association with cognition, especially in AD, the absence
of its beneficial effects in the central nervous system would suggest a
predisposition to cognitive impairment (26). Although Power et al. (9)
found lower serum leptin levels in patients with AD and vascular
dementia, more recently Teunissen et al. (27) reported that serum leptin
levels were not altered in a population of relatively young AD or
vascular dementia patients (mean age 60) compared to healthy subjects
and were not related to cognitive decline in that age group. In the
sample we presented here, similarly, the blood leptin levels of PD
patients were not lower than the control subjects and there was no
statistically significant difference in blood leptin levels of PD
patients and the controls.

Parkinson's disease patients had lower MoCA-TR scores than
controls, but leptin levels were not associated with cognition. In two
other prospective studies, higher leptin levels were associated with a
lower risk of dementia or cognitive impairment (28,29). Al Hazzouri et
al. (30) hypothesized that higher leptin would be associated with slower
rates of cognitive decline in aging Mexican Americans and found that a
higher baseline leptin level was associated with better cognitive
function over time for females and males without central obesity, as
measured by waist circumference. Leptin and insulin were found to have a
modulation effect on the hippocampal function. The regulation of
appetite and energy expenditure by leptin occurs by inhibiting serotonin
synthesis and releasing it in brainstem neurons. This is suggested as
leptin receptors were found also in brainstem serotoninergic neurons.
Leptin receptor mRNA expression has been demonstrated in substantia
nigra (31). Leptin has been shown to increase tyrosine hydroxylase
content and the regulation of dopamine transporter activity (32).
Therefore, leptin was shown to be able to modulate the mesolimbic
dopaminergic system (32,33).

To the best of our knowledge, there is no prior study in the
literature investigating the relationship between leptin levels and
cognition in PD patients. However our study has some limitations. First,
leptin levels may be subject to diurnal variation, although the blood
samples were taken during fasting in the morning at the same time for
all patients. Second, this is a cross sectional study with a small
sample size. Third, our study group had a relatively low age and more
than half of the patients were at a relatively early stage of the
disease. Leptin levels might be lower in patients with more advanced PD
and those with cognitive dysfunction.

In conclusion, cumulative data from our study and also from
previous reports suggest that the relationship between leptin levels and
cognition in neurodegenerative diseases such as AD and PD is still open
to debate. We think that additional longitudinal studies in different
larger populations need to be conducted to confirm the role of leptin as
a biomarker or as a possible treatment regimen for neurodegenerative
disorders in the future.

Ethics Committee Approval: Ethics committee approval was received
for this study from the ethics committee of Erenkoy Research and
Training Hospital for Neurological and Psychiatric Disorders.

Informed Consent: Written informed consent was obtained from
patients who participated in this study.